Accumulation of amyloid-β peptides is a dominant feature in the pathogenesis of Alzheimer’s disease; however, it is not clear how individual amyloid-β species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-β and full-length amyloid-β, depending on disease stage as well as brain area, and determined how these amyloid-β species respectively correlate with clinicopathological features of Alzheimer’s disease. To this end, the amounts of amyloid-β species and other proteins related to amyloid-β metabolism or Alzheimer’s disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer’s disease cases (n = 19), neurologically normal elderly without amyloid-β accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-β accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-β₄₂ and full-length amyloid-β₄₂ accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid-β₄₀ and full-length amyloid-β₄₀ accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-β₄₂ accumulation was increased in Alzheimer’s disease compared to pathological ageing, whereas cortical full-length amyloid-β₄₂ accumulation was comparable between Alzheimer’s disease and pathological ageing. Moreover, N-terminally truncated amyloid-β₄₂ were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-β₄₂ tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-β₄₂ species, represented by pyroglutamylated amyloid-β_11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-β₄₂ accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-β₄₂ accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-β₄₂ accumulation than those of other amyloid-β species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-β_11-x fibrils than full-length amyloid-β fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-β₄₂ in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-β₄₂ species have spatiotemporal accumulation patterns distinct from full-length amyloid-β₄₂, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-β species could play critical roles in the disease by linking other clinicopathological features of Alzheimer’s disease.

中文翻译：

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阿尔茨海默病中 N-截短和全长淀粉样蛋白-β42 的不同时空积累

β-淀粉样肽的积累是阿尔茨海默病发病机制中的一个主要特征；然而，尚不清楚各个β淀粉样蛋白种类如何积累并影响该疾病的其他神经病理学和临床特征。因此，我们根据疾病阶段和大脑区域比较了 N 端截短的淀粉样蛋白-β 和全长淀粉样蛋白-β 的积累，并确定了这些淀粉样蛋白-β 种类如何分别与阿尔茨海默病的临床病理特征相关。为此，通过酶联免疫吸附测定（ELISA）对淀粉样蛋白-β种类和其他与淀粉样蛋白-β代谢或阿尔茨海默氏病相关的蛋白质的量进行了定量，或者从理论上计算了12个大脑区域（包括新皮质、边缘和皮质下区域）阿尔茨海默病病例（n = 19）、神经系统正常但无β-淀粉样蛋白积累的老年人（正常衰老，n = 13）和神经系统正常但有皮质β-淀粉样蛋白积累的老年人（病理性衰老，n = 15）。我们观察到 N 端截短的淀粉样蛋白-β ₄₂和全长淀粉样蛋白-β ₄₂积累在疾病阶段和脑区域中分布不同，而 N 端截短的淀粉样蛋白-β ₄₀和全长淀粉样蛋白-β ₄₀积累显示出几乎相同的分布模式。与病理性衰老相比，阿尔茨海默病中皮质 N 末端截短的淀粉样蛋白-β ₄₂积累量增加，而阿尔茨海默病和病理性衰老之间的皮质全长淀粉样蛋白-β ₄₂积累量相当。此外，N端截短的淀粉样蛋白-β ₄₂更有可能在特定的大脑区域，特别是一些边缘区域积累更多，而全长淀粉样蛋白-β ₄₂倾向于在几个新皮质区域（包括额叶皮质）积累更多。免疫沉淀随后进行质谱分析表明，以焦谷氨酰化淀粉样蛋白-β _11-42为代表的几种 N 末端截短的淀粉样蛋白-β ₄₂种类在这些区域中富集，与 ELISA 结果一致。N 端截短的淀粉样蛋白-β ₄₂积累显示出与 BACE1 和脑啡肽酶显着的区域相关性，但与全长淀粉样蛋白-β ₄₂积累在区域性相关的 PSD95 没有显着相关性。有趣的是，tau 的积累以及更大程度上载脂蛋白 E（apoE，由APOE编码）的积累与 N 端截短的淀粉样蛋白 -β ₄₂的相关性更强其在大脑区域和疾病阶段的积累量均高于其他β淀粉样蛋白种类。一致地，免疫组织化学染色和体外结合测定表明，apoE 与焦谷氨酰化淀粉样蛋白-β _11-x原纤维共定位并结合得比全长淀粉样蛋白-β原纤维更牢固。对临床记录的回顾性审查表明，皮质区域 N 末端截短的淀粉样蛋白-β ₄₂的积累与疾病的发作、持续时间和认知评分相关。总的来说，N端截短的淀粉样蛋白-β ₄₂物种具有与全长淀粉样蛋白-β ₄₂不同的时空积累模式，这可能是由于控制它们在大脑中积累的机制不同。这些截短的β-淀粉样蛋白种类可能通过将阿尔茨海默病的其他临床病理特征联系起来，在该疾病中发挥关键作用。